PROJECT TWO SUMMARY/ABSTRACT Brain amyloidosis is a constant feature of Alzheimer's disease (AD); almost all patients with AD have high uptake of PET amyloid-binding radioligands such as PiB when scanned during life and extensive amyloid deposits at death. Cognitively normal individuals who have amyloid positive PET scans however present an unresolved conundrum: are they on the road to AD and will develop dementia given enough time, or do their brains have specific features that render them less vulnerable to the neurotoxic effects of A. This project will directly address this question by defining the neuropathological phenotype of individuals who are amyloid imaging positive and cognitively normal and document differences with those who are amyloid imaging positive and cognitively impaired. Further, by conducting detailed analyses of the pathological changes that occur during the earliest point in disease, we will be able to identify the evolution of changes that lead to dementia symptoms and identify useful surrogate markers to guide early diagnosis such as novel in vivo neuroimaging techniques. We will test these major hypotheses: 1) neuronal loss in the entorhinal cortex builds gradually during the preclinical phase of AD before an individual becomes symptomatic; 2) soluble oligomeric A levels will be greater in the impaired cases: 3) non-amyloid changes, such as tau lesions, will correlate closely with neuronal loss in amyloid imaging positive cases and 4) synaptic loss and glia activation will correlate with clinical symptoms and mark the transition to symptomatic stages; these changes will be less prominent in the resilient cases. In order to accomplish these goals, we have established working collaborations with four other ADCs (Mayo, University of Pittsburgh, Washington University and Columbia) to share clinical and neuroimaging data as well as brain tissue from three groups of subjects: Amyloid imaging positive and cognitively normal, amyloid imaging positive and cognitively impaired, and amyloid imaging negative and cognitively normal. By identifying neurobiologic factors that occur during the years after amyloid begins to accumulate but before symptoms manifest, we will set the stage for guiding the next generation of neuroimaging and other diagnostic tests as well as define rational targets for future effective therapeutic interventions.